Project Summary The long term goal of this project is to elucidate the role of aldehyde dehydrogenases (ALDH3A1 and ALDH1A1) in the ocular defense mechanism against ultraviolet radiation (UVR) toxicity. It is well known that UVR induces reactive oxygen species (ROS) that leads to membrane lipid peroxidation and accumulation of toxic aldehydes, such as 4-hydroxy-2- nonenal (4-HNE). Both ALDH3A1 and ALDH1A1 detoxify 4-HNE, which has been implicated in the pathogenesis of several diseases including cataract and degenerative retinal disease. During the last funding period, we have made novel and significant discoveries regarding the protective role of ALDH3A1 and ALDH1A1 against ocular oxidative stress. We found that both enzymes protect against UVR- and 4-HNE-induced cellular toxicity, and that, at least ALDH3A1, may act as UVR filter protecting other enzymes from inactivation. Finally, and most importantly, we found that Aldh3a1(-/-) and Aldh1a1(-/-)/Aldh3a1(-/-) knockout mice develop anterior and posterior subcapsular cataracts early in life, whereas Aldh1a1(-/-) knockout animals develop cataracts later in life. These novel data support our working hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via non- enzymatic (light filtering) and enzymatic (detoxification) functions.